Hypercholesterolemia is known to be one of the prime risk factors for ischemic cardiovascular disease, such as arteriosclerosis. Bile acid sequestrants have been used to treat this condition; they seem to be moderately effective, but they must be consumed in large quantities, i.e., several grams at a time, and they are not very palatable.
MEVACOR.RTM. (lovastatin), now commercially available, is one of a group of very active antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. These compounds inhibit early steps in cholesterol synthesis and may also inhibit the synthesis of other isoprenoids, such as dolichol, ubiquinone, and isopentenyl-t-RNA.
Squalene synthetase is the enzyme involved in the first committed step of the de novo cholesterol biosynthetic pathway. This enzyme catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene. The inhibition of this committed step to cholesterol should leave unhindered biosynthetic pathways to ubiquinone, dolichol and isopentenyl t-RNA.
Previous efforts at inhibiting squalene synthetase have employed compounds containing pyrophosphate or a pyrophosphate analog such as those described in P. Ortiz de Montellano et al., J. Med. Chem., 20, 243 (1977) and E. J. Corey and R. Volante, J. Am. Chem. Soc., 98, 1291 (1976). S. Biller (U.S. Pat. No. 4,871,721) describes isoprenoid (phosphinylmethyl) phosphonates as inhibitors of squalene synthetase. Other squalene synthetase inhibitors include the recently discovered Zaragozic acids. However, a need still remains for a more effective squalene synthetase inhibitor, i.e., one that provides a greater antihypercholesteremic effect and exhibits a good safety profile.
The present invention provides nonphosphorus containing quinuclidinyl-oxadiazole inhibitors of squalene synthetase. These compounds are known to be useful for the treatment of psychotic disorders or as intermediates in the synthesis of psycho-active agents.